Tolerance by Engaging Antigen During Cellular Homeostasis (TEACH)

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Anti-rejection medicines, also known as immunosuppressive drugs, are prescribed to organ transplant recipients to prevent rejection of the new organ. Long-term use of these medicines places transplant recipients at higher risk of serious infections and certain types of cancer.

The purpose of this study is to determine if:

it is safe to give mesenchymal stromal cells (MSCs) to kidney transplant recipients, and

the combination of the immunosuppressive (anti-rejection) study drugs plus the MSCs can allow a kidney transplant recipient to slowly reduce and/or then completely stop all anti-rejection drugs, without rejection of their kidney (renal) allograft, a process called "immunosuppression withdrawal".

Background:The most common problem following a kidney transplant is the development of acute or chronic rejection. Rejection is the immunologic reaction in which the body refuses to accept the transplanted organ. The body's immune system will make destructive antibodies that will attempt to attack the transplanted organ.

In order to prevent organ rejection, all patients receiving an allograft (a graft transplanted between genetically non-identical individuals of the same species) must take anti-rejection (immunosuppressive) therapy. These medications function by lowering the body's natural immune system. Often these medications are associated with significant side effects ranging from infections to cancer.

Study:

This is a single center, open label, dose-escalation clinical trial in 6 adult recipients of Human Leukocyte Antigen (HLA)- non-identical, living-donor renal allografts. All participants will receive induction therapy with alemtuzumab followed by maintenance therapy with sirolimus and belatacept.

A total of 3 dosing cohorts of 2 recipients each will receive 12 infusions of donor-derived MSCs starting on Day 42 post-transplant and every 4 weeks starting on Day 56 post-transplant, with a minimum of 7 days between the first and second MSC infusions.

The primary objective is to determine whether immune reconstitution after lymphocyte depletion in the setting of co-stimulatory blockade and systemic MSC-derived donor antigen can promote operational tolerance in recipients of kidney allografts.

Participants will be evaluated for eligibility for sirolimus withdrawal any time between week 52 and week 104 post-transplant. Participants who successfully complete sirolimus withdrawal will remain on belatacept monotherapy for at least 24 weeks before being assessed for eligibility to discontinue belatacept. Participants who successfully complete Immunosuppression Withdrawal (ISW) will then undergo 24 weeks of high frequency follow up followed by 132 weeks of standard follow up.

Study participation may continue for up to seven (7) years after kidney transplant surgery.

*** IMPORTANT NOTICE: *** The National Institute of Allergy and Infectious Diseases and the Immune Tolerance Network do not recommend the discontinuation of immunosuppressive therapy for recipients of cell, organ, or tissue transplants outside of physician-directed, controlled clinical studies. Discontinuation of prescribed immunosuppressive therapy can result in serious health consequences and should only be performed in certain rare circumstances, upon the recommendation and with the guidance of your health care provider.

These MSCs are a cellular product derived from bone marrow and propagated ex vivo using FDA-approved, clinically applicable methods. Their use in kidney transplantation has been associated with a good safety profile.

Other Names:

Donor-derived MSCs

human bone marrow derived MSCs

hBM-MSC

EPIC-MSC-ITN2015-IVF-0X

Drug: alemtuzumab

Alemtuzumab, 30 mg, given once intravenously (IV) over three hours. The infusion of alemtuzumab shall begin within 24 hours of transplantation surgery and shall be given prior to the first dose of belatacept.

Other Names:

Campath®

Lemtrada®

Drug: belatacept

Belatacept will be given as an intravenous (IV) infusion of 10mg /kg over 1 hour on transplantation postoperative Day 0, Days 5 and 14, then every 2 weeks (± 2 days) for 5 additional doses.Thereafter, belatacept will be given once every 4 weeks (± 5 days) at 10 mg/kg through 24 weeks post-transplant, then at 5 mg/kg every 4-weeks until the participant is evaluated for belatacept discontinuation.

If the first 3 infusions of 10^4 donor-derived Mesenchymal Stromal Cells (MSCs) cells/kg are well tolerated, this cohort of 2 participants will receive 12 infusions of 10^5 cells/kg every 4-weeks.

Biological: Donor-derived Mesenchymal Stromal Cells

These MSCs are a cellular product derived from bone marrow and propagated ex vivo using FDA-approved, clinically applicable methods. Their use in kidney transplantation has been associated with a good safety profile.

Other Names:

Donor-derived MSCs

human bone marrow derived MSCs

hBM-MSC

EPIC-MSC-ITN2015-IVF-0X

Drug: alemtuzumab

Alemtuzumab, 30 mg, given once intravenously (IV) over three hours. The infusion of alemtuzumab shall begin within 24 hours of transplantation surgery and shall be given prior to the first dose of belatacept.

Other Names:

Campath®

Lemtrada®

Drug: belatacept

Belatacept will be given as an intravenous (IV) infusion of 10mg /kg over 1 hour on transplantation postoperative Day 0, Days 5 and 14, then every 2 weeks (± 2 days) for 5 additional doses.Thereafter, belatacept will be given once every 4 weeks (± 5 days) at 10 mg/kg through 24 weeks post-transplant, then at 5 mg/kg every 4-weeks until the participant is evaluated for belatacept discontinuation.

If the first 3 infusions of 10^5 donor-derived Mesenchymal Stromal Cells (MSCs) cells/kg are well tolerated, this cohort of 2 participants will receive 12 infusions of 10^6 cells/kg every 4-weeks.

Biological: Donor-derived Mesenchymal Stromal Cells

These MSCs are a cellular product derived from bone marrow and propagated ex vivo using FDA-approved, clinically applicable methods. Their use in kidney transplantation has been associated with a good safety profile.

Other Names:

Donor-derived MSCs

human bone marrow derived MSCs

hBM-MSC

EPIC-MSC-ITN2015-IVF-0X

Drug: alemtuzumab

Alemtuzumab, 30 mg, given once intravenously (IV) over three hours. The infusion of alemtuzumab shall begin within 24 hours of transplantation surgery and shall be given prior to the first dose of belatacept.

Other Names:

Campath®

Lemtrada®

Drug: belatacept

Belatacept will be given as an intravenous (IV) infusion of 10mg /kg over 1 hour on transplantation postoperative Day 0, Days 5 and 14, then every 2 weeks (± 2 days) for 5 additional doses.Thereafter, belatacept will be given once every 4 weeks (± 5 days) at 10 mg/kg through 24 weeks post-transplant, then at 5 mg/kg every 4-weeks until the participant is evaluated for belatacept discontinuation.

Operational tolerance (to their kidney transplant) defined by participant remaining off all immunosuppression for 52 weeks after completion of Immunosuppression Withdrawal (ISW) with:

No evidence of biopsy-proven allograft rejection after initiation of ISW;

Acceptable renal function, defined as an estimated GFR > 60 ml/min/1.73cm^2 calculated using the CKD-EPI equation or a serum creatinine that has increased no more than 25% above baseline, as assessed at the week 52 visit after completion of ISW;

No evidence of sustained transplant renal derived pathologic proteinuria, defined as a persistent protein creatinine ratio of greater than 0.5; and

No Donor Specific Antibodies (DSA) at any time after completion of ISW.

Secondary Outcome Measures :

Proportion of Participants who Remain Off Immunosuppression [ Time Frame: From ISW completion to end of study participation (up to approximately 5 years) ]

For the duration of their study participation, after completion of immunosuppression withdrawal (ISW).

Proportion of Participants who Return to Immunosuppression [ Time Frame: From ISW completion to end of study participation (up to approximately 5 years) ]

Proportion of Participants who Achieve Belatacept Monotherapy [ Time Frame: 48 weeks from the time of last sirolimus dose ]

Belatacept monotherapy, defined as remaining on belatacept as the sole maintenance regimen for 48 weeks with:

No evidence of biopsy-proven allograft rejection, while on belatacept monotherapy;

Acceptable renal function, defined as an estimated GFR > 60 ml/min/1.73m^2 calculated using the CKD-EPI equation or a serum creatinine that has increased no more than 25% above baseline, as assessed at week 48 on belatacept monotherapy;

No evidence of sustained transplant renal derived pathologic proteinuria, defined as a persistent protein creatinine ratio of greater than 0.5, while on belatacept monotherapy; and

No Donor Specific Antibodies (DSA) at any time while on belatacept monotherapy.

Proportion of Participants who Die [ Time Frame: From kidney transplant with alemtuzumab induction to to completion of study (up to approximately 6.5 years) ]

This analysis will include all participants who provide informed consent for study participation and receive any form of study therapy including alemtuzumab, sirolimus, belatacept, or MSC infusions.

Time from Transplant to the First Episode of Rejection [ Time Frame: From kidney transplantation to completion of study (up to approximately 7 years) ]

Kaplan-Meier Analysis of time-to-occurrence to the first episode of kidney allograft rejection.

Incidence of Participants who Develop Donor Specific Antibody (DSA) [ Time Frame: From study enrollment to completion of study (up to approximately 7 years) ]

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

A negative serum or urine pregnancy test with sensitivity of less than 50 mIU/mL within 72 hours of start of study medication; and

Agreement to use contraception:

--- According to the FDA Office of Women's Health (http://www.fda.gov/birthcontrol), there are a number of birth control methods that are more than 80% effective

----Female recipients of child-bearing potential must consult with their physician and determine the most suitable method(s) from this list to be used for 18 months after the first dose of study therapy.

History of malignancy within 5 years of enrollment or any history of hematogenous malignancy or lymphoma; --Exception: Participants with curatively treated non-melanomatous skin cancer or curatively treated cervical carcinoma in situ may be enrolled.

Underlying renal disease with high likelihood of recurrence, including but not limited to:

primary focal segmental glomerulosclerosis (FSGS),

Type I or II membranoproliferative glomerulonephritis (MPGN),

hemolytic-uremic syndrome and

thrombotic thrombocytopenic purpura (HUS/TTP) syndrome. ---Subject(s) with end-stage renal disease (ESRD) of unknown etiology and/or has no histologically confirmed diagnosis, may be enrolled into the study as long as there are no clinical signs or symptoms consistent with excluded clinical diagnoses.

History of active M. tuberculosis:

--Participants with a history of latent M. tuberculosis (LTB) as defined by positive testing for tuberculosis using an approved IGRA blood test, such as QuantiFERON®-Gold TB or T-SPOT-TB assay must:

have completed treatment for LTB and

have a negative chest x-ray. ----All participants will undergo IGRA testing for M tuberculosis within 3 months prior to transplant.

Current or historical evidence of donor-specific antibody;

Immunosuppressive drug therapy within one year prior to enrollment.

May not be taking or have taken prednisone, cyclosporine A, tacrolimus, azathioprine, Mycophenolate Mofetil (MMF), cyclophosphamide, methotrexate, infliximab, etanercept, or other agents which have a primary therapeutic effect of immunosuppression in the year prior to transplantation.

May not have taken depletional anti-lymphocyte agents at any time.

---Exceptions:

Short (≤ 30 days) courses of topical or inhaled steroids are permitted, as are

Short oral or parental pulses for a documented hypersensitivity reaction.

Active autoimmune disease requiring ongoing immunosuppressive therapy or other conditions in which there is an anticipated need for immunosuppressive maintenance therapy;